Meibomian glands are a type of sebaceous gland (i.e. holocrine glands) located in the tarsal plate of the upper and lower eyelids. These glands are responsible for the supply of sebum, an oily substance that prevents evaporation of the eye's tear film, prevents tear spillage onto the cheek, and makes the closed lids airtight. There are approximately 50 glands on the upper eyelids and 25 glands on the lower eyelids. Meibomian glands are distinguished by grape-like clusters of acini on the mucocutaneous lid junction, and empty their lipid content (sebum) at this junction in order to coat the ocular surface via holocrine breakdown. The glands are anchored by cells that produce both polar and nonpolar lipids, which are then stored in lysosomes that merge into larger storage granules. As these cells continue to enlarge with lipid, they eventually rupture into the meibomian gland opening and spill the sebum over the ocular surface. These lipids are liquid at room temperature, typically with a melting point of between about 66 and 89° F., and are distributed over the ocular surface in a thin, smooth film called meibum. This meibum functions to prevent evaporation of the aqueous layer. Alterations in the meibum composition can have a profound effect on the health of the eyelid margins and ocular surface. Dysfunction of Meibomian glands in the general population is pretty high with some estimates as high as 39% (see, e.g., Hom M M et. al. Optom Vis Sci., 67(9), 710-2, 1990) with an increase in incidence in contact lens wearers (see, e.g., Ong B L. Optom Vis Sci., 73(3), 208-10, 1996).
Meibomian gland secretions form the lipid layer of tears and consist of polar and nonpolar lipids. The lipid type as well as fatty acid and alcohol composition of the meibum can affect tear parameters like initial formation of a composite monolayer with polar and nonpolar phases, adequate fluidity near body temperature, and the ability to undergo compression and expansion during blinking (see, e.g., McCulley et al., Adv Exp Med. Biol., 506 (Pt A), 373-8, 2002). In the human tear film lipid bilayer, the polar-phase lipids contain fatty acids with carbon chain lengths of 14-18 (C14-18) that are normally saturated. These properties are very important for effective polar lipid structuring and fluidity (melted physical state) at normal body temperature (see, e.g., McCulley et al., Adv Exp Med. Biol., 506(Pt A):373-8, 2002). Any alterations in the saturation of the fatty acids can lead to instability in the polar phase of lipids and thereby to instability of tears. In conditions like blepharitis that lead to meibomian gland dysfunction the normal fatty acid profile sometimes trends toward greater unsaturation. Any drug that can improve levels of saturated fatty acid would be beneficial to the treatment of meibomian gland disease.
Common complaints of patients suffering from Meibomian gland dysfunction include blurred or filmy vision, especially after performing near tasks, burning or foreign body sensations in the eye, excessive tearing, intolerance to contact lens, photophobia, and pain severe enough to awaken the person from sleep. Although patients with this condition usually have normal production of aqueous tears by their lacrimal glands, their Meibomian glands can atrophy and this is frequently accompanied by metaplasia of the ductal epithelium of these glands. Anterior erosion of the mucocutaneous junction of the eyelid is often noted, as well as eyelid and conjunctival infection, eyelid margin irregularity, corneal epithelial changes, and corneal vascularization. Common clinical tests to evaluate Meibomian gland dysfunction include Schirmer tear test, fluorescein staining (also known as ocular staining or conjunctival staining), and tear film break up time (TFBUT), each of which is briefly described below.
Schirmer tear test (STT): The Schirmer tear test is a measure of aqueous tear production. It is a clinical parameter used for dry eye and is done in normal or anesthetized eyes of patients to evaluate basal and reflex tearing. STT is performed by using standardized strips of filter paper with or without an impregnated dye and millimeter increments. The ends of the filter paper are placed in the conjuctival formix of each eye and amount of tears produced over one minute is measured. STT readings vary between species of animals. In dog it is typically greater than 10 mm of wetting/minute. Often in chronic Meibomian gland dysfunction the corneal epithelium shows significant dye uptake.
Fluorescein staining (a.k.a. ocular staining or conjunctival staining): This test is used to measure corneal epithelium integrity. Fluorescein dye is applied to the eye can be applied as a drop. Immediately after application of the dye, the patient is either allowed to blink or the eyelids are closed and opened manually. The excess fluorescein is then washed with eyewash and the corneal surface is then examined in a dark room with a cobalt blue filter fitted to a direct ophthalmoscope. Any uptake of the dye to the cornea is indicative of a disruption in the corneal surface epithelium. Often in chronic Meibomian gland dysfunction the corneal epithelium shows significant dye uptake.
Tear film break up time (TFBUT): This test is a subjective measure of precorneal tear film stability. TFBUT measures the time taken for the tears to evaporate from the surface of the cornea. In this test fluorescein dye is applied to the cornea and dye is allowed to pool on the cornea. Eyelids are opened and closed manually while eye examination is done with the blue light from cobalt blue fitted direct ophthalmoscope. The time taken from opening of the eyelids (formation of the green film on cornea) to the first appearance of a black area within the green stain of the cornea is measured. In humans TFBUT is typically less than 5 secs. In dogs it is 20 seconds. TFBUT is considered abnormal if the TFBUT is less than 3 secs in humans and less than 10 secs in dogs. Often in chronic Meibomian gland dysfunction the TFBUT is significantly decreased.
As Meibomian glands lining the eyelids produce lipids that promote the stability of the tears and reduce evaporation of the tear film, dysfunction of the Meibomian glands can lead to lipid insufficiency that destabilizes the tear film and causes decreases in tear film break-up time and evaporative dry eye (see, e.g., Sullivan et al., Ann. NY Acad. Sci., 966, 211-222, 2002).
Meibomian gland dysfunction may also be characterized by increased melting point of the lipids, causing solidification of the lipids and obstruction of the Meibomian gland secretion. This can result in cysts, infections and decreased lipid content in the tears. Meibomian gland dysfunction is also characterized by excess, abnormally turbid secretion that gets inspissated and plugs the meibomian orifices. This is followed by metaplasia of the meibomian ducts (abnormal keratinization). Blockage and resistance to flow results in inflammation and vascularization (redness) of tissue around the orifice. Inflammatory mediators accumulate in the tear film leading to damage of ocular surface. Sequlae of all these events is inflammatory scarring of the duct leading to stenosis. Initially glands swell and eventually atrophy.
Commonly used treatments include warm compresses to eyelid margins, mechanical probing of meibomian ducts, using infrared devices or chemicals to eyelid margins to induce tear lipid melting and secretion. For inflammation, glucocorticoids are used. If there is a bacterial component, antibiotics like penicillin, doxycycline and tetracyclines are used.
The physiology of the Meibomian gland function is believed to be under the control of androgens. Conditions of androgen deficiency that occur during aging, menopause, and androgen deprivation therapy for prostate cancer have been associated with evaporative dry eye (see, e.g., Sullivan et. al., Ann. NY Acad. Sci., 966, 211-222, 2002) indicating that androgens may play a major part in the etiology of this condition. Administration of 19-nortestosterone modulated the fatty acid profile in total and neutral lipid fractions in Meibomian gland secretions of rabbits (see, e.g., Sullivan et al., IOVS, 41(12), 3732-3742, 2000) indicating that androgen supplementation could be of benefit in treating such conditions.
Systemic androgen therapy with traditional steroidal agents is, however, associated with several undesirable side effects, including acne, seborrhea, hirsutism and concerns regarding prostate enlargement. The ability of 5α-reductase inhibitors to promote hair growth (topical) and treat prostatic disease (systemic) suggests that dihydrotestosterone (DHT), a potent full agonist for the androgen receptor and metabolite of testosterone, may be responsible for many of these virilizing effects.
Previous treatments of Meibomian gland dysfunctions were typically directed only to treatment of presumed infection of the eyelids or Meibomian glands, or had particular disadvantages that made such treatments of little use for long periods of time. For example, patients with Meibomian gland dysfunctions have been symptomatically treated with artificial tears, but these agents provide limited, if any, improvement. Topically applied glucocorticoids to the eyelids or ocular surface are effective as short-term pulse therapies. However, glucocorticoids are not good long-term solutions because of the potential side-effects e.g., cataract and glaucoma. Meibomian gland dysfunction is currently not curable or reversible; therefore, patients with this condition must be treated for life.
Hence, there is a need in the art to develop new methods of treating Meibomian gland dysfunctions. Applicants have developed compounds that provide a unique treatment approach for Meibomian gland dysfunction due to their ability to promote lipid production, lack of virilizing effects, and tissue selectivity. The methods described herein provide effective treatment for Meibomian gland dysfunctions with less undesirable side effects.